The Program Project Grant Structure and Function of Mechanosensitive Ion Channels brings together an array of technologies drawn from chemistry, biology, physics, and biotechnology to develop the most detailed structure/function analysis of an ion channel protein to date. Building on the foundation of the high resolution crystal structure of the Tb-MscL channel reported by Rees, the tools of structural biology, organic chemistry, determine how a channel responds to a stimulus and translates that stimulus into an observable signal. The four key components of the proposed program are: structure, function, synthesis, and redesign, and each of the parent MscL channel and on selected variants with the ultimate goal being a structure determination of the open state of the channel. High resolution electrophysiology techniques will correlate structure and function, and single molecule spectroscopy will provide unprecedented views of ion behavior. For the first time, total diversity involving both natural and unnatural modifications. A high throughput assay for MscL behavior will greatly aid the analysis of the structural variants prepared, and computer modeling will provide detailed insights into experimental observations. Since ion channels lie at the core of molecular neurobiology, the information obtained from this Project Grant will have far-reaching consequences. The list of neurological disorders associated with a malfunction in an ion channel protein is long and growing, and the information obtained here will be invaluable in understanding such disease states and in developing effective treatment strategies.